Pesticides And Parkinson s Disease In The Agricultural Health Study

农业和行动评估研究(FAME)是一项嵌套在农业健康研究中的帕金森病病例对照研究，这是一项针对89,000名有执照的杀虫剂施用者及其配偶的队列研究，旨在评估与农业相关的暴露在慢性病中的作用。FAME的具体目的是研究帕金森病与(I)农药暴露；(Ii)其他神经毒物，特别是金属；(Iii)生活方式因素，包括饮食、吸烟和咖啡因；(Iv)皮肤黑色素，以检查种族/民族差异；以及(V)参与多巴胺能神经传递、异种生物新陈代谢或异种生物特异性膜运输的基因的多态。 我们登记了115例病例和384名对照。帕金森病的诊断得到了运动障碍专家的证实。对照是从剩余的队列中随机抽取的样本，频率与年龄、性别和州的病例相匹配。接触情况的评估使用了来自三个互补来源的数据：(I)关于农药使用、其他暴露情况和生活方式的采访信息，这些信息已在AHS中收集；(Ii)血液样本，以测量有机氯和金属并进行DNA库；(Iii)新的电话采访，获得与帕金森病有关的特定杀虫剂以及其他神经毒物的信息。 农药与帕金森病：线粒体功能障碍和氧化应激是帕金森病的实验模型和遗传形式中涉及的病理生理机制。某些杀虫剂可能会影响这些机制，但还没有任何杀虫剂与人类的帕金森病有明确的联系。使用FAME数据，我们发现PD与使用一组抑制线粒体复合体I的杀虫剂(OR 1.7，95%CI，1.02.8)，包括鱼藤酮(OR 2.5，95%CI，1.34.7)和一组导致氧化应激的杀虫剂(OR 2.0，95%CI，1.23.6)有关，包括百草枯(OR 2.5；95%CI，1.44.7)。这是第一项显示帕金森病与鱼藤酮相关的研究，鱼藤酮是一种已知的线粒体毒物，用于最健壮的帕金森病动物模型之一。这项研究还扩展了之前关于帕金森和百草枯的工作，提供了更详细的数据，例如显示了剂量反应。我们的研究发现帕金森病与两组杀虫剂呈正相关，这两组农药是由先前所涉及的机制定义的，实验支持这些机制在帕金森病病理生理学中的作用。 百草枯、谷胱甘肽转移酶和PD：百草枯是世界上使用最广泛的除草剂之一。它通过氧化还原循环和氧化应激在啮齿类动物中产生帕金森病模型，并与人类的帕金森病风险有关。谷胱甘肽转移酶可保护细胞免受氧化应激，并有可能调节百草枯的毒性。我们研究了编码谷胱甘肽S转移酶M1(GSTM1)或T1(GSTT1)基因纯合缺失的个体中与使用百草枯相关的帕金森病风险。百草枯与GSTM1无相互作用。相反，GSTT1型显著改变了百草枯与帕金森病的关联(p交互作用=0.027)。在GSTT1功能正常的男性中，百草枯的OR为1.5(95%CI 0.63.6)，而在GSTT1纯合子缺失的男性中，OR为11.1(95%CI 3.044.6)。尽管需要复制，但我们的结果表明，在缺乏GSTT1的个体中，暴露于百草枯的帕金森病风险可能特别高。GSTT1缺失是常见的，可能会发现有大量亚群存在帕金森病的高风险，这些亚群是由百草枯等氧化应激源引起的。 膳食脂肪、农药暴露和帕金森病：膳食脂肪摄入可能直接或通过改变对环境神经毒物(包括杀虫剂)的反应来改变帕金森病的风险。使用FAME的数据，我们评估了89例确诊前10年的饮食和杀虫剂使用情况，或336例频率匹配的对照组的相应日期。PD与N-3多不饱和脂肪酸(PUFAs)呈负相关(OR0.4，95%CI0.2-0.8，最高三分位数与最低三分位数比较)和N-3前体亚麻酸(0.4，0.2-0.8)。此外，帕金森病与百草枯和鱼藤酮的关系被脂肪摄入量改变。在PUFA摄入量低于中位数的人群中，百草枯的OR为4.2(1.5-12)，而在摄入量较高的人群中(p交互作用=0.10)，百草枯的OR为1.2(0.4-3.4)。在饱和脂肪摄入量高于中位数的人群中，鱼藤酮的OR为5.8(2.3-15)，而在摄入量较低的人群中，鱼藤酮的OR为1.5(0.5-4.2)(p交互作用=0.02)。因此，高多不饱和脂肪酸摄入量可以减轻神经炎症，降低与百草枯相关的帕金森病风险。相比之下，高饱和脂肪摄入量可能会增加氧化应激，增加与鱼藤酮相关的帕金森病风险。 α-突触核蛋白、头部损伤和帕金森病：散发性帕金森病与头部损伤和SNCA Rep1有关，SNCA Rep1是编码α-突触核蛋白基因启动子区域的一个多态二核苷酸微卫星。我们评估了SNCA Rep1改变散发性脑损伤和帕金森病风险之间关系的假设。来自FAME的数据与第二项帕金森病病例对照研究、环境关联研究和帕金森病风险研究的数据结合在一起，使用病例对照历史访谈(SEARCH)。与以前的报告一致，与中长Rep1相比，短Rep1基因与PD风险降低相关，而长Rep1基因与风险增加相关。头部损伤与总体上的帕金森病无显著关联(OR 1.3，95%CI 0.91.8)，在REP1短或中长的患者中也不是如此。然而，在Rep1长的患者中，颅脑损伤与帕金森病密切相关(OR 3.5，95%CI 1.49.2，p交互作用=0.02)。既有颅脑损伤又有Rep1长的个体比没有危险因素的个体早4.9年被诊断出来(p=0.03)。虽然头部损伤本身与PD风险无关，但我们的数据表明，当α-突触核蛋白水平较高时，如Rep1扩张者，头部损伤可能会启动和/或加速神经退行性变。

The Farming and Movement Evaluation Study (FAME) is a case-control study of PD nested in the Agricultural Health Study, a cohort study of 89,000 licensed pesticide applicators and spouses designed to evaluate the role of farming-related exposures in chronic disease. The specific aims of FAME were to examine the relationship of PD to (i) pesticide exposure; (ii) other neurotoxicants, particularly metals; (iii) lifestyle factors including diet, smoking, and caffeine; (iv) skin melanin, to examine racial/ethnic differences; and (v) polymorphisms in genes involved in dopaminergic neurotransmission, xenobiotic metabolism, or xenobiotic-specific membrane transport. We enrolled 115 cases and 384 controls. PD diagnosis was verified by movement disorder specialists. Controls were a random sample from the remaining cohort, frequency matched to cases by age, sex, and state. Exposure was evaluated using data from three complementary sources: (i) interview information on pesticide use, other exposures, and lifestyle already collected in the AHS; (ii) blood samples to measure organochlorines and metals and for DNA banking; and (iii) new telephone interviews which obtained information on specific pesticides implicated in PD as well as other neurotoxicants. Pesticides and PD: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of PD. Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Using FAME data, we found that PD was associated with use of a group of pesticides that inhibit mitochondrial complex I (OR 1.7, 95% CI, 1.02.8), including rotenone (OR 2.5, 95% CI, 1.34.7), and with use of a group of pesticides that cause oxidative stress (OR 2.0, 95% CI, 1.23.6), including paraquat (OR 2.5; 95% CI, 1.44.7). This is the first study to show an association of PD with rotenone, a known mitochondrial toxicant used in one of the most robust animal models of PD. The study also extends previous work on PD and paraquat with more detailed data, showing for example a dose-response. Our finding that PD was positively associated with two groups of pesticides defined by mechanisms previously implicated experimentally supports a role for these mechanisms in PD pathophysiology. Paraquat, glutathione transferases, and PD: Paraquat is one of the most widely used herbicides worldwide. It produces a PD model in rodents through redox cycling and oxidative stress and is associated with PD risk in humans. Glutathione transferases provide cellular protection against oxidative stress and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione-S-transferase M1 (GSTM1) or T1 (GSTT1). There was no interaction of paraquat with GSTM1. In contrast, GSTT1 genotype significantly modified the association of paraquat with PD (p-interaction=0.027). In men with functional GSTT1, the OR for paraquat was 1.5 (95% CI 0.63.6), while in men with homozygous GSTT1 deletion, the OR was 11.1 (95% CI 3.044.6). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. The GSTT1 deletion is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat. Dietary fat, pesticide exposure, and PD: Dietary fat intake may modify PD risk directly or by altering the response to environmental neurotoxicants including pesticides. Using data from FAME, we evaluated diet and pesticide use 10 years before diagnosis in 89 cases or a corresponding date in 336 frequency-matched controls. PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4, 95% CI 0.2-0.8 for highest vs lowest tertile) and the N-3 precursor -linolenic acid (0.4, 0.2-0.8). Moreover, associations of PD with paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction=0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake (p-interaction=0.02). Thus, high PUFA intake, which may mitigate neuroinflammation, moderated the PD risk associated with paraquat. In contrast, high saturated fat intake, which may increase oxidative stress, increased PD risk associated with rotenone. alpha-synuclein, head injury, and PD: Sporadic PD is associated with both head injury and SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding alpha-synuclein. We evaluated the hypothesis that SNCA Rep1 modifies the association between head injury and PD risk in sporadic cases. Data from FAME were combined with data from a second case-control study of PD, the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH). Consistent with prior reports, short Rep1 genotype was associated with reduced PD risk and long Rep1 with increased risk, relative to medium-length Rep1. Head injury was not significantly associated with PD overall (OR 1.3, 95% CI 0.91.8), nor among those with short or medium-length Rep1. However, head injury was strongly associated with PD in those with long Rep1 (OR 3.5, 95% CI 1.49.2, p-interaction=0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p=0.03). While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of alpha-synuclein are high, as in those with Rep1 expansion.